PROJECT DESCRIPTION/ABSTRACT Dry eye disease (DED) and other ocular surface diseases (OSD) are common conditions that can reduce visual function and quality of life. Commonly used ophthalmic preservatives can cause a toxic epitheliopathy that results in OSD. The treatment of these diseases is primarily through the use of palliative measures. Great opportunity exists to improve the quality of life of many patients by developing novel treatments. DED and OSD are associated with significant dysfunction of corneal epithelia and inflammatory changes on the ocular surface. Many of these changes are induced by hyperosmolarity, desiccation and inflammatory insults. Histatin is a family of peptides found primarily in saliva and is known to have significant wound healing and anti-infective properties. Little data exist on the mechanisms of action of histatin peptides, though some effects are thought to be mediated through as yet unknown receptors. We have found that these peptides can reduce inflammatory changes associated with exposures of toxic preservatives to the ocular surface and in experimental conditions that mimic DED. We have also found a potential novel ligand-receptor interaction for histatin peptides. Our long term objective is to develop a new class of DED and OSD therapeutics which are non-toxic and anti- inflammatory. Our central hypothesis is that histatin peptides can ameliorate the inflammatory effects of toxic and inflammatory insults to corneal epithelia in vitro and in vivo. We will utilize well vetted models of toxic epitheliopathy, hyperosmolarity and desiccation in order to show the efficacy of histatin peptides in treating OSDs. We will also undertake studies to find receptors for histatin peptide. The proposed research is innovative as it is the first study to investigate the use of histatin peptides in the treatment of DED and OSD. These studies are significant because they will advance the development of new therapeutics through the use of rigorous and well defined methods in clinically relevant translational models of disease and validate a novel receptor-ligand relationship.